The goal of the proposed research is to determine how the interferon regulatory factor 5(IRF5) lupus risk variant translates into biological risk of systemic lupus erythematosus (SLE). Genome wide association studies (GWAS) have identified IRF5 as one of the most strongly associated genes with susceptibility to SLE. Although the genetic association of IRF5 with lupus is clear, the exact mechanism by which IRF5 risk variant promotes susceptibility for lupus is still unknown. We hypothesize that IRF8 could be a negative regulatory factor of IRF5 activity under normal conditions, while in lupus the IRF5 exon 6 risk variants are capable of escaping this negative regulation thereby activating type I IFNs leading to aberrant immune activation. To address this question, we will (SA1) characterize IRF5 exon 6 variants in pDCs using molecular and biochemical approaches, (SA2) investigate the effects of IRF8 on IRF5 exon 6 variants, and (SA3) effect of IRF5 exon 6 variation on IRF5 activation in SLE patients. If IRF8 blocks IRF5 activation, this will be a significant step to gain the mechanistic understanding of aberrant production type I IFNs and immune activation in lupus.